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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors
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Archives of Cardiovascular Disease (2017) xxx, xxx—xxx
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CLINICAL RESEARCH
Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Sarcoïdoses cardiaques : diagnostic, prise en charge thérapeutique et facteurs pronostiques Catherine Chapelon-Abric a,∗, Damien Sene b, David Saadoun a, Philippe Cluzel c, Olivier Vignaux d, Nathalie Costedoat-Chalumeau e, Jean-Clarles Piette f, Patrice Cacoub g a
Département de Médecine Interne et d’Immunologie Clinique, CHU Pitié-Salpétrière, 47—83, boulevard de l’Hôpital, 75013 Paris, France b Département Médecine Interne, Hôpital Lariboisière, 75475 Paris, France c Service de Radiologie, CHU Pitié-Salpétrière, 75013 Paris, France d Service de Radiologie, Hôpital Cochin, 75014 Paris, France e Département Médecine Interne, Hôpital Cochin, 75014 Paris, France f Département Médecine Interne, CHU Pitié-Salpétrière, 75013 Paris, France g UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Département de Médecine Interne et d’Immunologie Clinique, Sorbonne Universités, UPMC Université Paris, CHU Pitié-Salpétrière, 75005 Paris, France Received 26 February 2016; received in revised form 25 October 2016; accepted 17 December 2016
KEYWORDS Cardiac sarcoidosis; Steroids; Methotrexate;
Summary Background. — Cardiac sarcoidosis (CS) is a severe localization, observed mostly in cardiology departments. Despite appropriate cardiological treatment, CS is a potentially life-threatening condition, and accounts for 13—85% of sarcoidosis-related deaths.
Abbreviations: CI, confidence interval; CS, cardiac sarcoidosis; ECG, electrocardiogram; IST, immunosuppressive therapy; MRI, magnetic resonance imaging; PET, positron emission tomography. ∗ Corresponding author. E-mail address: [email protected] (C. Chapelon-Abric). http://dx.doi.org/10.1016/j.acvd.2016.12.014 1875-2136/© 2017 Published by Elsevier Masson SAS.
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Cyclophosphamide; Relapse; Survival rate
MOTS CLÉS Sarcoïdose cardiaque ; Corticoïdes ; Méthotrexate ; Cyclophosphamide ; Rechute taux de guérison
Aims. — This retrospective study aimed to give an overview of CS in a non-cardiac unit, to analyse the effect of first-line immunosuppressive treatment on outcome and survival and to evaluate factors associated with relapses. Methods. — From 534 cases of sarcoidosis, we selected 59 patients with CS according to ‘‘2006 international criteria’’. We performed an in-depth analysis regarding symptoms, physical signs and cardiac investigation results. Patients were followed for a median period of 60 months. Results. — The median age at cardiac signs was 42 years. Echocardiography abnormalities, isotopic defects and abnormal magnetic resonance imaging findings were observed in 81%, 84% and 92% of patients, respectively. First-line treatment included steroids alone in 24 patients and steroids plus immunosuppressive therapy in 35 patients. Forty-seven (80%) patients recovered; 12 stabilized or worsened. The recovery rate was 75% in the steroids alone group versus 83% in the steroids plus immunosuppressive therapy group. Five (9%) patients died during follow-up, with two deaths attributed to CS. The overall 1- and 5-year survival rates were 98% and 92%, respectively. Conclusion. — Our series of patients with CS who received steroids alone or combined with immunosuppressive therapy had a good prognosis, with an overall 5-year survival rate of 92%. The recovery rate was 85%, with no significant difference between patients treated with steroids alone or plus immunosuppressive therapy. © 2017 Published by Elsevier Masson SAS.
Résumé Contexte. — La sarcoïdose cardiaque est une localisation sévère, le plus souvent prise en change en cardiologie. Malgré un traitement cardiologique approprié, le pronostic est sombre avec un taux de mortalité de 13 à 85 %. Objectifs. — Étude rétrospective permettant de : (1) présenter les sarcoïdoses cardiaques en médecine interne ; (2) analyser l’impact des immunosuppresseurs sur le pronostic et la survie. Méthodes. — Dans une cohorte de 534 sarcoïdoses, 59 patients répondaient aux critères internationaux de 2006. L’analyse a porté sur les signes cliniques et les investigations cardiologiques. Ils ont été suivis pendant une période médiane de 60 mois. Résultats. — L’âge médian lors des signes cardiaques est de 42 ans. L’échocardiographie, les examens isotopiques, et l’IRM ont été anormaux respectivement dans 81 %, 84 % et 92 % des cas. De première intention, ils ont rec ¸u soit de la prednisone dans 24 cas, soit de la prednisone associée à un immunosuppresseur dans 35 cas. Quatre-vingt pour cent ont évolué favorablement, 12 se sont stabilisés ou aggravés. Le taux de guérison a été de 75 % dans le groupe prednisone seule contre 83 % dans le groupe prednisone plus immunosuppresseur. Cinq patients sont décédés, deux sont en rapport avec la sarcoïdose cardiaque. L’espérance de vie à 1 et 5 ans est respectivement de 98 et 92 %. Conclusion. — Dans cette série, les patients traités par prednisone seule ou associée à un autre immunosuppresseur ont un bon pronostic avec une espérance de vie à 5 ans de 92 %. Le taux de guérison ne diffère pas entre les deux groupes de traitement. © 2017 Publi´ e par Elsevier Masson SAS.
Background Evidence of non-caseating granulomas in affected organs characterizes sarcoidosis, which is described as a systemic chronic granulomatous disease of unknown aetiology. In patients with sarcoidosis, cardiac involvement has been reported in 3—40% of cases in clinical series according to diagnostic criteria and procedures [1—4], and in up to 30% of cases in pathology series [5]. Cardiac sarcoidosis (CS) is a potentially life-threatening condition, and accounts
for 13—25% of sarcoidosis-related deaths in the USA and 85% in Japan [6,7]. Most CS series are published by cardiology departments, with patients presenting predominant cardiac expression and receiving specific cardiac treatment combined, in most cases, with steroids [2,3,8,9]. However, CS is usually observed within the scope of severe multivisceral sarcoidosis. The aim of the present study was to better characterize CS in patients seen in a non-cardiac unit and its related extracardiac sarcoidosis conditions. We also aimed to analyse the impact of immunosuppressive therapy
Please cite this article in press as: Chapelon-Abric C, et al. Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors. Arch Cardiovasc Dis (2017), http://dx.doi.org/10.1016/j.acvd.2016.12.014
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors (IST) on short-term responses and relapses and long-term outcome.
Methods Study design and patients A cohort of 534 patients with definite systemic sarcoidosis, seen in a single internal medicine department between 1995 and 2014, was studied retrospectively. From this large cohort, we selected patients who presented with CS based on the ‘‘2006 international criteria’’ adapted and revised from Hiraga et al. [1] (Table 1) [2]. We performed an in-depth analysis of these patients with CS, regarding symptoms and physical signs, electrocardiogram (ECG) results, echocardiography, isotopic examinations, magnetic resonance imaging (MRI) and 18 F-FDG positron emission tomography (PET) scans. Overall, 128/534 (24%) patients with sarcoidosis had either cardiac symptoms/signs or an abnormal ECG, but only 59/128 patients had definite CS according to the ‘‘2006 international criteria’’, and were included in the present analysis (Fig. 1). For all included patients, cardiac involvement was documented with cardiac symptoms/signs, chest X-ray, ECG, 24-hour ECG, two-dimensional echocardiography and at least one other imaging method (e.g. thallium scanning, MRI). CS was considered as severe when patients presented a functional or vital risk (i.e. cardiac insufficiency and/or ventricular arrhythmia and/or severe atrioventricular block). Other data collected at diagnosis and during followup included age, sex, ethnic group, extracardiac organs affected by sarcoidosis and first-line treatment. No patients had co-morbid conditions that could induce cardiac disease or pulmonary hypertension. For all patients, the following cardiac diseases were excluded: ischaemic, hypertensive, diabetic, valvular or alcoholic cardiomyopathy, Lyme disease, amyloidosis, dermatopolymyositis, polyangiitis with granulomatosis, Takayasu disease, rheumatoid arthritis and myocarditis. The authors had full access to all data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis.
Treatment First-line treatment included steroids (1 mg/kg/day prednisone equivalent) or steroids plus IST. Immunosuppressive drugs included cyclophosphamide, methotrexate, mycophenolate mofetil and cyclosporine. Intravenous cyclophosphamide (500—700 mg/m2 /month) was given to patients who needed a rapid therapeutic effect, and it was combined with methylprednisolone (1000 mg/day for 3 consecutive days). In the other cases, methotrexate (0.3 mg/kg/week) was given to allow rapid steroid tapering, which was started 8—12 weeks after methotrexate initiation. Mycophenolate mofetil (2000—3000 mg/day) was given in two cases (one patient with renal sarcoidosis and one patient who declined any injection). One patient received cyclosporine (5 mg/kg/day) after heart transplantation. For complete and partial responders, steroid therapy was gradually tapered over several months, with a target
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dose of < 10 mg/day of prednisone equivalent. Patients who responded to first-line treatment with cyclophosphamide (cumulative dose of 6—12 g) were switched to methotrexate (0.3 mg/kg/week) or mycophenolate mofetil (2000 mg/day). Progressive tapering of steroids and/or IST was then proposed, with the objective of attaining minimal treatment at year 1. When necessary, usual cardiac therapies were added: angiotensin-converting enzyme inhibitors or angiotensin receptor inhibitors, beta-blockers, antiarrhythmic therapy, calcium channel blockers, diuretics, warfarin, pacemakers, implantable defibrillators, radiofrequency ablation or cardiac transplantation. Patients were evaluated every 3 months during the first year of treatment, then every 6 months for 2 years, then at least once a year, and at each suspected relapse.
Outcome After a median follow-up period of 60.0 months (95% confidence interval [CI] 42—86 months), the response of CS to treatment was analysed according to multiple criteria, including New York Heart Association class, ECG, 24-hour ECG, echocardiography and heart imaging. Patients were classified as complete responders in case of absence of cardiac clinical symptoms and normalization of all abnormal baseline examinations. Partial responders were defined by the absence of cardiac clinical symptoms with the persistence of abnormal heart imaging. The recovery group included complete and partial responders; all other cases were defined as non-responders. A CS relapse was defined by the reappearance of abnormalities on ECG, 24-hour ECG, echocardiography and at least one other imaging method (e.g. thallium scanning, MRI) on previously healed lesions. Deaths were analysed in-depth, to be classified as either related to CS/systemic sarcoidosis or to another nonsarcoidosis cause.
Statistical analysis Continuous variables were compared using the Wilcoxon rank-sum test or the Kruskal—Wallis test, and categorical variables were compared using Fisher’s exact test or the Chi2 test, as appropriate. All tests were two-tailed and a P-value ≤ 0.05 was considered statistically significant. A stepwise multiple logistic regression analysis was used to assess independent associations. Rates of event-free survival (death, recovery or relapse) over time were plotted by the Kaplan—Meier method, and were compared using the log-rank test. A Cox proportional hazards multiple regression model was used to evaluate risk factors (relative risk) associated with CS relapse or non-response to treatment. All ® statistical analyses were performed using MedCalc , version 11.1.1.0 (MedCalc Software, Mariakerke, Belgium).
Results Baseline characteristics Main baseline CS features and extracardiac sarcoidosis localizations are detailed in Table 2. The median age at
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C. Chapelon-Abric et al. Table 1 Summary of the 2006 revised guidelines for diagnosis of cardiac sarcoidosis of the Japanese Ministry of Health and Welfare [11]. Pathological diagnosis
Clinical diagnosis
Major criteria
Minor criteria
CS is confirmed when the cardiac biopsy specimen demonstrates non-caseating granuloma with histological or clinical diagnosis of extracardiac sarcoidosis Endomyocardial biopsy demonstrating non-caseating epithelioid granuloma CS is diagnosed, in the absence of an endomyocardial biopsy specimen or in the absence of typical granulomas on cardiac biopsy, when extracardiac sarcoidosis has been proven and a combination of major or minor diagnostic criteria has been satisfied, as follows: two or more than two of four major criteria OR one of the four major criteria and two or more of the minor criteria Advanced atrioventricular block Basal thinning of the ventricular septum Positive cardiac gallium uptake LVEF < 50% Abnormal ECG findings, including ventricular tachycardia, multifocal frequent premature ventricular contractions, complete right bundle branch block, pathological Q waves or abnormal axis deviation Abnormal echocardiogram demonstrating regional wall motion abnormalities, ventricular aneurysm or unexplained increased in wall thickness Perfusion defects detected by myocardial scintigraphy Delayed gadolinium enhancement of the myocardium on cardiac MRI scanning Interstitial fibrosis or monocyte infiltration greater than moderate grade by endomyocardial biopsy
CS: cardiac sarcoidosis; ECG: electrocardiogram; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging.
Figure 1.
Flow chart and outcome of the study population. CS: cardiac sarcoidosis.
sarcoidosis diagnosis was 39 years; the median age at CS diagnosis was 42 years. Patients were mainly Caucasian (42%) or black (42%), with a female/male ratio of 0.55. CS was diagnosed simultaneously to (49%) or after (41%) the extracardiac sarcoidosis. Pulmonary involvement was noted in 78% of patients, with abnormal functional respiratory tests (28%) and decreased diffusion capacity for carbon monoxide (diffusing capacity of the lung for carbon monoxide [DLCO], 34%), although no pulmonary hypertension could be
observed. Extracardiac sarcoidosis involvement was mostly diffuse, with three or more extracardiac organs involved in 61% of patients. The New York Heart Association classification of cardiac failure was abnormal in 20 (33%) cases (class II, 12 cases; class III, six cases; and class IV, two cases). Tachycardia was confirmed by ECG in 25 cases. The extrapulmonary and extracardiac manifestations of sarcoidosis involved the central neurological system (51%), the skin (29%), the eyes (25%) and the liver/spleen (20%).
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Table 2 Variables
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Baseline features of the study population. All (n = 59)
Age at sarcoidosis diagnosis (years) 39 (33—46) Age at CS diagnosis (years) 42 (37—46) Sex ratio: female/male (n/n) 0.55 (20/39) Ethnic origin Caucasian 25 (42) Black 25 (42) Maghreb 7 (12) Asian 2 (4) Sarcoidosis extracardiac involvement Abnormal chest X-rays 46 (78) Neurological 30 (51) Peripheral nodes 22 (37) General symptoms 21 (36) Skin 17 (29) Eyes 15 (25) Joints 11 (19) Liver/spleen 12 (20) Nose 4 (7) Kidney 3 (5) Number of organs affected by sarcoidosis (heart excluded) ≤1 11 (19) 12 (19) 2 3 14 (24) 4 14 (24) ≥5 8 (13) Time relationship between CS and sarcoidosis diagnosis 6 (10) Before Simultaneously 29 (49) After 24 (41)
Steroids alone (n = 24)
Steroids + IST (n = 35)
38 (34—48) 41.5 (38—47) 0.85 (11/13)
39 (31—48) 42 (33—49) 0.35 (9/26)
9 13 1 1
(38) (54) (4) (4)
16 12 6 1
(46) (34) (17) (3)
22 9 6 9 7 5 7 3 1 1
(92) (38) (25) (38) (29) (21) (29) (13) (4) (4)
24 21 16 12 10 10 4 9 3 2
(69) (60) (43) (34) (29) (29) (11) (26) (9) (6)
5 1 10 7 1
(21) (4) (42) (29) (4)
6 11 4 7 7
(17) (31) (11) (20) (20)
4 (17) 8 (33) 12 (50)
2 (6) 21 (60) 12 (34)
Data are expressed as median (95% confidence interval) or number (%), unless indicated otherwise. CS: cardiac sarcoidosis; IST: immunosuppressive therapy.
Baseline ECG and cardiac morphological abnormalities are detailed in Table 3. A normal ECG was noted in only 17% of cases. In other cases, we observed ‘‘2006 international criteria’’ ECG abnormalities in 46 patients, and ‘‘non-typical’’ abnormalities in 48 patients, including sinus tachycardia (n = 23), abnormal repolarization (n = 12), atrial arrhythmias (n = 10) and left ventricular hypertrophy (n = 3). Of note, for the latter, because of the disease severity and despite atypical electrical signs, we decided to pursue cardiac investigations. Sinus tachycardia was associated with ‘‘2006 international criteria’’ ECG criteria in 15 cases, atrial arrhythmias in three cases and abnormal repolarization in two cases. Sinus tachycardia was the only abnormal ECG sign in five cases, always associated with abnormal echocardiography and/or scintigraphy and/or MRI. Echocardiography abnormalities were observed in 81% of patients. Scintigraphic myocardial ‘‘2006 international criteria’’ abnormalities were observed in 84% of patients, mostly patchy localized defects. Myocardial MRI, abnormal in 92% of patients, showed delayed gadolinium enhancement of the myocardium in eight cases (‘‘2006 international criteria’’). In patients without gadolinium enhancement, MRI showed left ventricular dysfunction (31 cases) and/or
localized hypokinesia (seven cases) and/or pericardial involvement (three cases). In 46 patients, the three cardiac morphological investigations (echocardiography, scintigraphy and MRI) were performed simultaneously, and 29/46 (63%) patients had abnormal results on all three examinations. During heart surgery, CS was confirmed.
First-line treatment Steroids were given alone to 24 patients, while 35 patients received a combination of steroids plus IST. The median steroid therapy duration was 54.5 months (95% CI: 34—84 months) for patients receiving steroids alone and 44 months (95% CI: 36—86 months) for those receiving steroids plus IST. The IST was intravenous cyclophosphamide in 20 patients, methotrexate in 12 patients, mycophenolate mofetil in two patients and cyclosporine A in the post-cardiac transplantation period in one patient. The choice of intravenous cyclophosphamide was based on the risk of mortality or morbidity related to systemic extracardiac/extraneurological sarcoidosis (10 cases), CS (six cases) and neurological sarcoidosis (four cases). Methotrexate was mostly used for a steroid-sparing strategy.
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C. Chapelon-Abric et al. Table 3
Baseline electrocardiographic and morphological abnormalities.
Cardiac examination
n/n (%)
Details
Abnormal ECG
49/59 (83)
Abnormal echocardiography
48/59 (81)
Abnormal scintigraphy
47/56 (84)
Abnormal MRI
45/49 (92)
Ventricular arrhythmia (n = 17) Atrioventricular block (n = 15) Right bundle branch block (n = 10) Axial deviation (n = 4) Abnormal Q wave (n = 0) Atrial arrhythmiaa (n = 10) Abnormal T wavesa (n = 12) Left ventricular hypertrophya (n = 3) Hypokinesia (n = 25) Left ventricular dysfunction (n = 38) Septal thickness (n = 12) Abnormal relaxationa (n = 10) Shining echoa (n = 5) Left atrial dilatationa (n = 2) Pericardial effusiona (n = 1) Diffuse defect (n = 6) Localized defect (n = 41) Delayed gadolinium enhancement (n = 8) Left ventricular dysfunctiona (n = 31) Localized hypokinesiaa (n = 7) Pericardial enhancementa (n = 3)
ECG: electrocardiogram; MRI: magnetic resonance imaging. a Not included in the ‘‘2006 international criteria’’ for cardiac sarcoidosis.
alone versus 83% (29/35) for those who received steroids plus IST (11/12 cases with methotrexate and 17/20 cases with cyclophosphamide). The univariate analysis failed to identify significant differences between patients treated with steroids alone and those who received steroids plus IST, and between patients who recovered and those who did not recover (Table 4). One transplanted patient died a few days after transplantation. Another patient survived after cardiac transplantation and remained in remission for 13 years; he then developed a relapse of sarcoidosis on the cardiac transplant, with good control under cyclophosphamide. Some patients developed side effects (e.g. high blood pressure, moderate obesity, non-insulin-dependent diabetes), which did not lead to IST being stopped.
Relapse after first-line treatment Figure 2. Death: Kaplan—Meier curve analysis of the survival rate of patients with cardiac sarcoidosis.
A permanent pacemaker was implanted in four patients and a cardiac defibrillator was fitted in three patients. Cardiac transplantation was performed in two patients.
Outcome After a median follow-up period of 60.0 months, the overall 1- and 5-year survival rates were 98% and 92%, respectively (Fig. 2). Recovery was achieved by 47 (80%) patients, 10 (17%) had stabilization and two (3%) worsened. The recovery rate was 75% (18/24) for patients who received steroids
A relapse of CS was diagnosed in 23 (39%) patients, after a median 19-month period (95% CI: 12—45 months). At the time of CS relapse, steroids had been stopped in five patients (2—48 months). Eighteen patients were still receiving steroids (≤ 10 mg/day for 12 patients; 15—35 mg/day for six patients). Compared with patients who did not relapse, patients who relapsed were younger (39 years [95% CI: 32—45 years] vs. 46 years [95% CI: 39—52 years]; P = 0.09) and were more frequently female (48% vs. 25%; P = 0.09). After multivariable analysis, a relapse of CS was associated with an age at CS diagnosis of ≤ 46 years (odds ratio: 0.28; 95% CI: 0.08 − 0.92; P = 0.036) and with female sex (odds ratio: 3.2; 95% CI: 0.97—10.5; P = 0.055) (Table 5). Using a Cox multivariable model, the relative risk of relapsing at any time was higher in black patients (relative risk: 2.3; 95% CI: 1—5;
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Table 4
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Main features of patients with cardiac sarcoidosis who did not recover compared with those who did recover.
Variables
Recovery− (n = 12)
Recovery+ (n = 47)
Univariate analysis P
Age (years) Women Caucasian Black Central nervous system Abnormal echocardiography Decreased LVEF Abnormal myocardial scintigraphy Abnormal myocardial MRI Immunosuppressant as first-line therapy Cyclophosphamide Methotrexate Steroids duration < 24 months Steroids duration (months)
45 (39—57) 4 (33) 4 (33) 6 (50) 7 (58) 11 (92) 9 (75) 11/12 (92) 9/11 (82) 6 (50) 3 (25) 2 (17) 3 (25) 42 (27—67)
41 (34—47) 17 (36) 21 (45) 19 (40) 23 (49) 37 (79) 38 (81) 36/44 (82) 35/38 (92) 29 (62) 17 (36) 11 (23) 8 (17) 55 (66—116)
0.29 1.00 0.53 0.74 0.75 0.43 0.69 0.67 0.31 0.52 0.73 1.00 0.68 0.18
Data are expressed as median (95% confidence interval) or number (%). LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; Recovery−: patients who did not recover; Recovery+: patients who did recover.
Table 5
Main features of patients with cardiac sarcoidosis who relapsed compared with those who did not relapse.
Variables
Age (years) Age at CS diagnosis ≤ 46 years Women Caucasian Black Abnormal echocardiography Decreased LVEF Abnormal myocardial scintigraphy Abnormal myocardial MRI IST Cyclophosphamide Methotrexate
Relapse+ (n = 23)
39 (32—45) 6 (26) 11 (48) 7 (30) 12 (52) 18 (78) 17 (74) 20/23 (87) 19/21 (90) 12 (52) 6 (26) 5 (22)
Relapse− (n = 36)
46 (39—52) 19 (53) 9 (25) 18 (50) 13 (36) 30 (83) 30 (83) 27/33 (82) 25/28 (89) 23 (64) 14 (39) 8 (22)
Univariate analysis
Multivariable analysis
P
OR (95% CI)
0.09 0.06 0.09 0.18 0.28 0.73 0.51 0.72 1.00 0.42 0.40 1.00
P
0.28 (0.08—0.92)0.036 3.2 (0.97—10.5) 0.055
Data are expressed as median (95% confidence interval) or number (%), unless indicated otherwise. CI: confidence interval; IST: immunosuppressive therapy; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; OR: odds ratio; Relapse−: patients who did not relapse; Relapse+: patients who did relapse.
P = 0.04) and in black female patients (relative risk: 3.0; 95% CI: 1.1—8; P = 0.017) (Fig. 3A and B).
Death Five (9%) patients died during follow-up, with two deaths being directly attributable to CS: one sudden death and one death a few days after heart transplantation. The other deaths were the result of asthma (one case), cerebral haemorrhage (one case) and lymphoma (one case).
Discussion The present study reports data from the largest cohort of patients with CS seen in a non-cardiac department. The main conclusions drawn from this study are as follows: CS is usually observed within the field of severe multivisceral sarcoidosis; patients with CS frequently present with unusual clinical and imaging cardiac signs; IST, including steroids, leads to a good prognosis; and long-term followup of patients with CS is mandatory, given the significant risk of relapse.
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Figure 3. Relapse: Kaplan—Meier curve analysis showing the higher risk of cardiac relapse after first-line therapy. A. In black patients. B. In mostly black female patients.
Our series included patients with severe extracardiac sarcoidosis manifestations, as 60% of patients had at least three organ involvements [10]. Neurological involvement was noted in > 50% of cases [2]. These results underline the importance of systematically searching for cardiac manifestations in patients with severe extracardiac sarcoidosis. This strategy permits earlier diagnosis of CS, before abnormal ECG and cardiac symptoms appear. In our series, early diagnosis of CS probably explains the high rate of patients with moderate symptoms [2], as well as the low rate of patients with a decreased left ventricular ejection fraction by MRI (31%) compared with Japanese reports (48—51%) [8,9]. Of note, the ‘‘2006 international criteria’’ appear to be insufficient to detect patients with CS presenting with ‘‘minor’’ cardiological signs [11]. Using only these criteria would have led us to stop our cardiological investigations,
although patients finally proved to have cardiac involvement of sarcoidosis. For example, pericardial effusion is not in the ‘‘2006 international criteria’’, although pericardial biopsies confirmed a granulomatous infiltration; we considered isolated sinus tachycardia (90—110 bpm) as abnormal in the field of systemic disease. Some international criteria are not defined, such as atrial arrhythmias [12]. Other criteria are poorly defined, and are not taken into account: the evaluation of left ventricular ejection fraction (by echocardiography or MRI); isotopic defects and the absence of reversibility during stress or dipyridamole infusion; and the localization and/or nodular aspect of delayed gadolinium enhancement of the myocardium on MRI. The ‘‘2006 international criteria’’ appear useful for patients with severe CS, who are mostly seen in cardiology departments [4,11—13], but, surprisingly, sudden death is not a major criterion. In addition, these criteria do not allow evaluation of the severity of the localization, and do not take into account both CS and extracardiac sarcoidosis. In asymptomatic patients, ECG and echocardiography have low sensitivity and may be normal. All recent publications underline the prognostic and diagnostic values of the FDG PET scan [14—16], eventually associated to scintigraphy [14] and cardiac MRI [17—22]. In a cohort of 71 patients presenting an abnormal PET scan, Blankstein et al. [14] reported 27 ventricular tachycardias and eight deaths after a 1.5-year follow-up. Therefore, a multimodal approach seems mandatory to encompass the diversity of abnormal investigations in sarcoidosis patients with cardiac involvement [11,16,23]; this will also allow the exclusion of other causes of cardiomyopathy. The treatment of CS is challenging, as it always includes cardiac treatments and sometimes immunosuppressants. In our series, all patients received the usual cardiac therapies, including invasive treatment (15% of cases), such as a pacemaker [24], an implantable defibrillator [4,25], radiofrequency ablation [18,21] or cardiac surgery [3,4,26]. The efficacy of steroid treatment for CS has not been evaluated in prospective or controlled studies. However, there is a growing body of evidence to support its efficacy in preserving cardiac function and in treating CS-related cardiac insufficiency [27] and atrioventricular block [13,28] to prevent ventricular tachycardia [29] and improve imaging abnormalities [16,23,30]. The dose of steroids used is mostly between 0.5 and 1.0 mg/kg/day [2,9,11] for a prolonged duration [13]. The role of IST in the therapeutic arsenal of patients with CS remains a matter of debate. Most of our patients received intravenous cyclophosphamide [11]. Tumour necrosis factor antagonists have also been proposed [31,32]. In less severe localizations, and in order to spare steroids, methotrexate proved effective and was well tolerated. Mycophenolate mofetil may also be proposed in such a situation. Of note, in our series, no patient who received IST developed a severe infection or an adverse effect. With the exception of the recent study by Nagai et al. [13], comparing treatment with a low-dose of methotrexate and steroids, there is no comparative study in patients with CS that has demonstrated a survival rate improvement. CS is known to have a bad prognosis, with an estimated mortality rate of up to 50% [6,7]. We and others have shown that in patients who received steroids alone or combined with IST, the 5-year survival rate reached 60—90% [4,8,9,13], with a reduced risk of major adverse cardiac events [33].
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors To our knowledge, an analysis of CS relapses and their related factors has never been carried out. A relapse was noted in 39% of our patients, independent of the type of first-line treatment. Two main factors were associated with CS relapses: female sex and black origin, the latter being associated with a more severe disease. Interestingly, these factors are also considered to be associated with a higher risk of sarcoidosis occurrence and a greater severity of systemic sarcoidosis [5]. Study limitations: the present study has some limitations. The retrospective nature of this study is a well-known limitation. Although we report one of the largest series of CS, we acknowledge the need for controlled randomized studies to better define investigation and treatment strategies. We do believe that the cornerstone of CS treatment remains steroid treatment, and that IST should be discussed in cases of severe cardiac or extracardiac disease, for relapse or for steroid-sparing strategies. Another limitation was the small number of patients, but this should be analysed considering the rarity of CS. To respect the ‘‘2006 international criteria’’, we excluded patients with cardiac signs and probable CS in 69 cases. This raises the question about the type of investigations for CS early diagnosis, as the use of cardiac MRI and PET scans may show very early morphological and functional abnormalities without an ECG abnormality [23]. The new consensus statement on the diagnosis and management of arrhythmias associated with CS may help to include CS [34].
Conclusions In conclusion, in this large series of patients, CS has a good prognosis, with an overall 5-year survival rate of 92%. The recovery rate was > 75%, with no significant difference between patients treated with steroids alone or steroids plus IST. Close monitoring is mandatory, particularly in female or black patients, as they appear to be at higher risk of relapse. Immunosuppressant maintenance treatment was well tolerated, and certainly helped to stabilize the granulomatosis, which cannot be cured.
Sources of funding None.
Acknowledgements D. Sène and C. Chapelon-Abric acquired and analysed data, wrote and critically revised the manuscript and provided final approval of the version to be published. D. Saadoun, N. Costedoat-Chalumeau, J.-C. Piette and P. Cacoub included patients in the study, critically revised the manuscript and provided final approval of the version to be published. P. Cluzel and O. Vignaux reviewed cardiac MRI data, critically revised the manuscript and provided final approval of the version to be published.
Disclosure of interest The authors declare that they have no competing interest.
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Available online at
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CLINICAL RESEARCH
Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Sarcoïdoses cardiaques : diagnostic, prise en charge thérapeutique et facteurs pronostiques Catherine Chapelon-Abric a,∗, Damien Sene b, David Saadoun a, Philippe Cluzel c, Olivier Vignaux d, Nathalie Costedoat-Chalumeau e, Jean-Clarles Piette f, Patrice Cacoub g a
Département de Médecine Interne et d’Immunologie Clinique, CHU Pitié-Salpétrière, 47—83, boulevard de l’Hôpital, 75013 Paris, France b Département Médecine Interne, Hôpital Lariboisière, 75475 Paris, France c Service de Radiologie, CHU Pitié-Salpétrière, 75013 Paris, France d Service de Radiologie, Hôpital Cochin, 75014 Paris, France e Département Médecine Interne, Hôpital Cochin, 75014 Paris, France f Département Médecine Interne, CHU Pitié-Salpétrière, 75013 Paris, France g UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Département de Médecine Interne et d’Immunologie Clinique, Sorbonne Universités, UPMC Université Paris, CHU Pitié-Salpétrière, 75005 Paris, France Received 26 February 2016; received in revised form 25 October 2016; accepted 17 December 2016
KEYWORDS Cardiac sarcoidosis; Steroids; Methotrexate;
Summary Background. — Cardiac sarcoidosis (CS) is a severe localization, observed mostly in cardiology departments. Despite appropriate cardiological treatment, CS is a potentially life-threatening condition, and accounts for 13—85% of sarcoidosis-related deaths.
Abbreviations: CI, confidence interval; CS, cardiac sarcoidosis; ECG, electrocardiogram; IST, immunosuppressive therapy; MRI, magnetic resonance imaging; PET, positron emission tomography. ∗ Corresponding author. E-mail address: [email protected] (C. Chapelon-Abric). http://dx.doi.org/10.1016/j.acvd.2016.12.014 1875-2136/© 2017 Published by Elsevier Masson SAS.
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Cyclophosphamide; Relapse; Survival rate
MOTS CLÉS Sarcoïdose cardiaque ; Corticoïdes ; Méthotrexate ; Cyclophosphamide ; Rechute taux de guérison
Aims. — This retrospective study aimed to give an overview of CS in a non-cardiac unit, to analyse the effect of first-line immunosuppressive treatment on outcome and survival and to evaluate factors associated with relapses. Methods. — From 534 cases of sarcoidosis, we selected 59 patients with CS according to ‘‘2006 international criteria’’. We performed an in-depth analysis regarding symptoms, physical signs and cardiac investigation results. Patients were followed for a median period of 60 months. Results. — The median age at cardiac signs was 42 years. Echocardiography abnormalities, isotopic defects and abnormal magnetic resonance imaging findings were observed in 81%, 84% and 92% of patients, respectively. First-line treatment included steroids alone in 24 patients and steroids plus immunosuppressive therapy in 35 patients. Forty-seven (80%) patients recovered; 12 stabilized or worsened. The recovery rate was 75% in the steroids alone group versus 83% in the steroids plus immunosuppressive therapy group. Five (9%) patients died during follow-up, with two deaths attributed to CS. The overall 1- and 5-year survival rates were 98% and 92%, respectively. Conclusion. — Our series of patients with CS who received steroids alone or combined with immunosuppressive therapy had a good prognosis, with an overall 5-year survival rate of 92%. The recovery rate was 85%, with no significant difference between patients treated with steroids alone or plus immunosuppressive therapy. © 2017 Published by Elsevier Masson SAS.
Résumé Contexte. — La sarcoïdose cardiaque est une localisation sévère, le plus souvent prise en change en cardiologie. Malgré un traitement cardiologique approprié, le pronostic est sombre avec un taux de mortalité de 13 à 85 %. Objectifs. — Étude rétrospective permettant de : (1) présenter les sarcoïdoses cardiaques en médecine interne ; (2) analyser l’impact des immunosuppresseurs sur le pronostic et la survie. Méthodes. — Dans une cohorte de 534 sarcoïdoses, 59 patients répondaient aux critères internationaux de 2006. L’analyse a porté sur les signes cliniques et les investigations cardiologiques. Ils ont été suivis pendant une période médiane de 60 mois. Résultats. — L’âge médian lors des signes cardiaques est de 42 ans. L’échocardiographie, les examens isotopiques, et l’IRM ont été anormaux respectivement dans 81 %, 84 % et 92 % des cas. De première intention, ils ont rec ¸u soit de la prednisone dans 24 cas, soit de la prednisone associée à un immunosuppresseur dans 35 cas. Quatre-vingt pour cent ont évolué favorablement, 12 se sont stabilisés ou aggravés. Le taux de guérison a été de 75 % dans le groupe prednisone seule contre 83 % dans le groupe prednisone plus immunosuppresseur. Cinq patients sont décédés, deux sont en rapport avec la sarcoïdose cardiaque. L’espérance de vie à 1 et 5 ans est respectivement de 98 et 92 %. Conclusion. — Dans cette série, les patients traités par prednisone seule ou associée à un autre immunosuppresseur ont un bon pronostic avec une espérance de vie à 5 ans de 92 %. Le taux de guérison ne diffère pas entre les deux groupes de traitement. © 2017 Publi´ e par Elsevier Masson SAS.
Background Evidence of non-caseating granulomas in affected organs characterizes sarcoidosis, which is described as a systemic chronic granulomatous disease of unknown aetiology. In patients with sarcoidosis, cardiac involvement has been reported in 3—40% of cases in clinical series according to diagnostic criteria and procedures [1—4], and in up to 30% of cases in pathology series [5]. Cardiac sarcoidosis (CS) is a potentially life-threatening condition, and accounts
for 13—25% of sarcoidosis-related deaths in the USA and 85% in Japan [6,7]. Most CS series are published by cardiology departments, with patients presenting predominant cardiac expression and receiving specific cardiac treatment combined, in most cases, with steroids [2,3,8,9]. However, CS is usually observed within the scope of severe multivisceral sarcoidosis. The aim of the present study was to better characterize CS in patients seen in a non-cardiac unit and its related extracardiac sarcoidosis conditions. We also aimed to analyse the impact of immunosuppressive therapy
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors (IST) on short-term responses and relapses and long-term outcome.
Methods Study design and patients A cohort of 534 patients with definite systemic sarcoidosis, seen in a single internal medicine department between 1995 and 2014, was studied retrospectively. From this large cohort, we selected patients who presented with CS based on the ‘‘2006 international criteria’’ adapted and revised from Hiraga et al. [1] (Table 1) [2]. We performed an in-depth analysis of these patients with CS, regarding symptoms and physical signs, electrocardiogram (ECG) results, echocardiography, isotopic examinations, magnetic resonance imaging (MRI) and 18 F-FDG positron emission tomography (PET) scans. Overall, 128/534 (24%) patients with sarcoidosis had either cardiac symptoms/signs or an abnormal ECG, but only 59/128 patients had definite CS according to the ‘‘2006 international criteria’’, and were included in the present analysis (Fig. 1). For all included patients, cardiac involvement was documented with cardiac symptoms/signs, chest X-ray, ECG, 24-hour ECG, two-dimensional echocardiography and at least one other imaging method (e.g. thallium scanning, MRI). CS was considered as severe when patients presented a functional or vital risk (i.e. cardiac insufficiency and/or ventricular arrhythmia and/or severe atrioventricular block). Other data collected at diagnosis and during followup included age, sex, ethnic group, extracardiac organs affected by sarcoidosis and first-line treatment. No patients had co-morbid conditions that could induce cardiac disease or pulmonary hypertension. For all patients, the following cardiac diseases were excluded: ischaemic, hypertensive, diabetic, valvular or alcoholic cardiomyopathy, Lyme disease, amyloidosis, dermatopolymyositis, polyangiitis with granulomatosis, Takayasu disease, rheumatoid arthritis and myocarditis. The authors had full access to all data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis.
Treatment First-line treatment included steroids (1 mg/kg/day prednisone equivalent) or steroids plus IST. Immunosuppressive drugs included cyclophosphamide, methotrexate, mycophenolate mofetil and cyclosporine. Intravenous cyclophosphamide (500—700 mg/m2 /month) was given to patients who needed a rapid therapeutic effect, and it was combined with methylprednisolone (1000 mg/day for 3 consecutive days). In the other cases, methotrexate (0.3 mg/kg/week) was given to allow rapid steroid tapering, which was started 8—12 weeks after methotrexate initiation. Mycophenolate mofetil (2000—3000 mg/day) was given in two cases (one patient with renal sarcoidosis and one patient who declined any injection). One patient received cyclosporine (5 mg/kg/day) after heart transplantation. For complete and partial responders, steroid therapy was gradually tapered over several months, with a target
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dose of < 10 mg/day of prednisone equivalent. Patients who responded to first-line treatment with cyclophosphamide (cumulative dose of 6—12 g) were switched to methotrexate (0.3 mg/kg/week) or mycophenolate mofetil (2000 mg/day). Progressive tapering of steroids and/or IST was then proposed, with the objective of attaining minimal treatment at year 1. When necessary, usual cardiac therapies were added: angiotensin-converting enzyme inhibitors or angiotensin receptor inhibitors, beta-blockers, antiarrhythmic therapy, calcium channel blockers, diuretics, warfarin, pacemakers, implantable defibrillators, radiofrequency ablation or cardiac transplantation. Patients were evaluated every 3 months during the first year of treatment, then every 6 months for 2 years, then at least once a year, and at each suspected relapse.
Outcome After a median follow-up period of 60.0 months (95% confidence interval [CI] 42—86 months), the response of CS to treatment was analysed according to multiple criteria, including New York Heart Association class, ECG, 24-hour ECG, echocardiography and heart imaging. Patients were classified as complete responders in case of absence of cardiac clinical symptoms and normalization of all abnormal baseline examinations. Partial responders were defined by the absence of cardiac clinical symptoms with the persistence of abnormal heart imaging. The recovery group included complete and partial responders; all other cases were defined as non-responders. A CS relapse was defined by the reappearance of abnormalities on ECG, 24-hour ECG, echocardiography and at least one other imaging method (e.g. thallium scanning, MRI) on previously healed lesions. Deaths were analysed in-depth, to be classified as either related to CS/systemic sarcoidosis or to another nonsarcoidosis cause.
Statistical analysis Continuous variables were compared using the Wilcoxon rank-sum test or the Kruskal—Wallis test, and categorical variables were compared using Fisher’s exact test or the Chi2 test, as appropriate. All tests were two-tailed and a P-value ≤ 0.05 was considered statistically significant. A stepwise multiple logistic regression analysis was used to assess independent associations. Rates of event-free survival (death, recovery or relapse) over time were plotted by the Kaplan—Meier method, and were compared using the log-rank test. A Cox proportional hazards multiple regression model was used to evaluate risk factors (relative risk) associated with CS relapse or non-response to treatment. All ® statistical analyses were performed using MedCalc , version 11.1.1.0 (MedCalc Software, Mariakerke, Belgium).
Results Baseline characteristics Main baseline CS features and extracardiac sarcoidosis localizations are detailed in Table 2. The median age at
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C. Chapelon-Abric et al. Table 1 Summary of the 2006 revised guidelines for diagnosis of cardiac sarcoidosis of the Japanese Ministry of Health and Welfare [11]. Pathological diagnosis
Clinical diagnosis
Major criteria
Minor criteria
CS is confirmed when the cardiac biopsy specimen demonstrates non-caseating granuloma with histological or clinical diagnosis of extracardiac sarcoidosis Endomyocardial biopsy demonstrating non-caseating epithelioid granuloma CS is diagnosed, in the absence of an endomyocardial biopsy specimen or in the absence of typical granulomas on cardiac biopsy, when extracardiac sarcoidosis has been proven and a combination of major or minor diagnostic criteria has been satisfied, as follows: two or more than two of four major criteria OR one of the four major criteria and two or more of the minor criteria Advanced atrioventricular block Basal thinning of the ventricular septum Positive cardiac gallium uptake LVEF < 50% Abnormal ECG findings, including ventricular tachycardia, multifocal frequent premature ventricular contractions, complete right bundle branch block, pathological Q waves or abnormal axis deviation Abnormal echocardiogram demonstrating regional wall motion abnormalities, ventricular aneurysm or unexplained increased in wall thickness Perfusion defects detected by myocardial scintigraphy Delayed gadolinium enhancement of the myocardium on cardiac MRI scanning Interstitial fibrosis or monocyte infiltration greater than moderate grade by endomyocardial biopsy
CS: cardiac sarcoidosis; ECG: electrocardiogram; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging.
Figure 1.
Flow chart and outcome of the study population. CS: cardiac sarcoidosis.
sarcoidosis diagnosis was 39 years; the median age at CS diagnosis was 42 years. Patients were mainly Caucasian (42%) or black (42%), with a female/male ratio of 0.55. CS was diagnosed simultaneously to (49%) or after (41%) the extracardiac sarcoidosis. Pulmonary involvement was noted in 78% of patients, with abnormal functional respiratory tests (28%) and decreased diffusion capacity for carbon monoxide (diffusing capacity of the lung for carbon monoxide [DLCO], 34%), although no pulmonary hypertension could be
observed. Extracardiac sarcoidosis involvement was mostly diffuse, with three or more extracardiac organs involved in 61% of patients. The New York Heart Association classification of cardiac failure was abnormal in 20 (33%) cases (class II, 12 cases; class III, six cases; and class IV, two cases). Tachycardia was confirmed by ECG in 25 cases. The extrapulmonary and extracardiac manifestations of sarcoidosis involved the central neurological system (51%), the skin (29%), the eyes (25%) and the liver/spleen (20%).
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Table 2 Variables
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Baseline features of the study population. All (n = 59)
Age at sarcoidosis diagnosis (years) 39 (33—46) Age at CS diagnosis (years) 42 (37—46) Sex ratio: female/male (n/n) 0.55 (20/39) Ethnic origin Caucasian 25 (42) Black 25 (42) Maghreb 7 (12) Asian 2 (4) Sarcoidosis extracardiac involvement Abnormal chest X-rays 46 (78) Neurological 30 (51) Peripheral nodes 22 (37) General symptoms 21 (36) Skin 17 (29) Eyes 15 (25) Joints 11 (19) Liver/spleen 12 (20) Nose 4 (7) Kidney 3 (5) Number of organs affected by sarcoidosis (heart excluded) ≤1 11 (19) 12 (19) 2 3 14 (24) 4 14 (24) ≥5 8 (13) Time relationship between CS and sarcoidosis diagnosis 6 (10) Before Simultaneously 29 (49) After 24 (41)
Steroids alone (n = 24)
Steroids + IST (n = 35)
38 (34—48) 41.5 (38—47) 0.85 (11/13)
39 (31—48) 42 (33—49) 0.35 (9/26)
9 13 1 1
(38) (54) (4) (4)
16 12 6 1
(46) (34) (17) (3)
22 9 6 9 7 5 7 3 1 1
(92) (38) (25) (38) (29) (21) (29) (13) (4) (4)
24 21 16 12 10 10 4 9 3 2
(69) (60) (43) (34) (29) (29) (11) (26) (9) (6)
5 1 10 7 1
(21) (4) (42) (29) (4)
6 11 4 7 7
(17) (31) (11) (20) (20)
4 (17) 8 (33) 12 (50)
2 (6) 21 (60) 12 (34)
Data are expressed as median (95% confidence interval) or number (%), unless indicated otherwise. CS: cardiac sarcoidosis; IST: immunosuppressive therapy.
Baseline ECG and cardiac morphological abnormalities are detailed in Table 3. A normal ECG was noted in only 17% of cases. In other cases, we observed ‘‘2006 international criteria’’ ECG abnormalities in 46 patients, and ‘‘non-typical’’ abnormalities in 48 patients, including sinus tachycardia (n = 23), abnormal repolarization (n = 12), atrial arrhythmias (n = 10) and left ventricular hypertrophy (n = 3). Of note, for the latter, because of the disease severity and despite atypical electrical signs, we decided to pursue cardiac investigations. Sinus tachycardia was associated with ‘‘2006 international criteria’’ ECG criteria in 15 cases, atrial arrhythmias in three cases and abnormal repolarization in two cases. Sinus tachycardia was the only abnormal ECG sign in five cases, always associated with abnormal echocardiography and/or scintigraphy and/or MRI. Echocardiography abnormalities were observed in 81% of patients. Scintigraphic myocardial ‘‘2006 international criteria’’ abnormalities were observed in 84% of patients, mostly patchy localized defects. Myocardial MRI, abnormal in 92% of patients, showed delayed gadolinium enhancement of the myocardium in eight cases (‘‘2006 international criteria’’). In patients without gadolinium enhancement, MRI showed left ventricular dysfunction (31 cases) and/or
localized hypokinesia (seven cases) and/or pericardial involvement (three cases). In 46 patients, the three cardiac morphological investigations (echocardiography, scintigraphy and MRI) were performed simultaneously, and 29/46 (63%) patients had abnormal results on all three examinations. During heart surgery, CS was confirmed.
First-line treatment Steroids were given alone to 24 patients, while 35 patients received a combination of steroids plus IST. The median steroid therapy duration was 54.5 months (95% CI: 34—84 months) for patients receiving steroids alone and 44 months (95% CI: 36—86 months) for those receiving steroids plus IST. The IST was intravenous cyclophosphamide in 20 patients, methotrexate in 12 patients, mycophenolate mofetil in two patients and cyclosporine A in the post-cardiac transplantation period in one patient. The choice of intravenous cyclophosphamide was based on the risk of mortality or morbidity related to systemic extracardiac/extraneurological sarcoidosis (10 cases), CS (six cases) and neurological sarcoidosis (four cases). Methotrexate was mostly used for a steroid-sparing strategy.
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C. Chapelon-Abric et al. Table 3
Baseline electrocardiographic and morphological abnormalities.
Cardiac examination
n/n (%)
Details
Abnormal ECG
49/59 (83)
Abnormal echocardiography
48/59 (81)
Abnormal scintigraphy
47/56 (84)
Abnormal MRI
45/49 (92)
Ventricular arrhythmia (n = 17) Atrioventricular block (n = 15) Right bundle branch block (n = 10) Axial deviation (n = 4) Abnormal Q wave (n = 0) Atrial arrhythmiaa (n = 10) Abnormal T wavesa (n = 12) Left ventricular hypertrophya (n = 3) Hypokinesia (n = 25) Left ventricular dysfunction (n = 38) Septal thickness (n = 12) Abnormal relaxationa (n = 10) Shining echoa (n = 5) Left atrial dilatationa (n = 2) Pericardial effusiona (n = 1) Diffuse defect (n = 6) Localized defect (n = 41) Delayed gadolinium enhancement (n = 8) Left ventricular dysfunctiona (n = 31) Localized hypokinesiaa (n = 7) Pericardial enhancementa (n = 3)
ECG: electrocardiogram; MRI: magnetic resonance imaging. a Not included in the ‘‘2006 international criteria’’ for cardiac sarcoidosis.
alone versus 83% (29/35) for those who received steroids plus IST (11/12 cases with methotrexate and 17/20 cases with cyclophosphamide). The univariate analysis failed to identify significant differences between patients treated with steroids alone and those who received steroids plus IST, and between patients who recovered and those who did not recover (Table 4). One transplanted patient died a few days after transplantation. Another patient survived after cardiac transplantation and remained in remission for 13 years; he then developed a relapse of sarcoidosis on the cardiac transplant, with good control under cyclophosphamide. Some patients developed side effects (e.g. high blood pressure, moderate obesity, non-insulin-dependent diabetes), which did not lead to IST being stopped.
Relapse after first-line treatment Figure 2. Death: Kaplan—Meier curve analysis of the survival rate of patients with cardiac sarcoidosis.
A permanent pacemaker was implanted in four patients and a cardiac defibrillator was fitted in three patients. Cardiac transplantation was performed in two patients.
Outcome After a median follow-up period of 60.0 months, the overall 1- and 5-year survival rates were 98% and 92%, respectively (Fig. 2). Recovery was achieved by 47 (80%) patients, 10 (17%) had stabilization and two (3%) worsened. The recovery rate was 75% (18/24) for patients who received steroids
A relapse of CS was diagnosed in 23 (39%) patients, after a median 19-month period (95% CI: 12—45 months). At the time of CS relapse, steroids had been stopped in five patients (2—48 months). Eighteen patients were still receiving steroids (≤ 10 mg/day for 12 patients; 15—35 mg/day for six patients). Compared with patients who did not relapse, patients who relapsed were younger (39 years [95% CI: 32—45 years] vs. 46 years [95% CI: 39—52 years]; P = 0.09) and were more frequently female (48% vs. 25%; P = 0.09). After multivariable analysis, a relapse of CS was associated with an age at CS diagnosis of ≤ 46 years (odds ratio: 0.28; 95% CI: 0.08 − 0.92; P = 0.036) and with female sex (odds ratio: 3.2; 95% CI: 0.97—10.5; P = 0.055) (Table 5). Using a Cox multivariable model, the relative risk of relapsing at any time was higher in black patients (relative risk: 2.3; 95% CI: 1—5;
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors Table 4
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Main features of patients with cardiac sarcoidosis who did not recover compared with those who did recover.
Variables
Recovery− (n = 12)
Recovery+ (n = 47)
Univariate analysis P
Age (years) Women Caucasian Black Central nervous system Abnormal echocardiography Decreased LVEF Abnormal myocardial scintigraphy Abnormal myocardial MRI Immunosuppressant as first-line therapy Cyclophosphamide Methotrexate Steroids duration < 24 months Steroids duration (months)
45 (39—57) 4 (33) 4 (33) 6 (50) 7 (58) 11 (92) 9 (75) 11/12 (92) 9/11 (82) 6 (50) 3 (25) 2 (17) 3 (25) 42 (27—67)
41 (34—47) 17 (36) 21 (45) 19 (40) 23 (49) 37 (79) 38 (81) 36/44 (82) 35/38 (92) 29 (62) 17 (36) 11 (23) 8 (17) 55 (66—116)
0.29 1.00 0.53 0.74 0.75 0.43 0.69 0.67 0.31 0.52 0.73 1.00 0.68 0.18
Data are expressed as median (95% confidence interval) or number (%). LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; Recovery−: patients who did not recover; Recovery+: patients who did recover.
Table 5
Main features of patients with cardiac sarcoidosis who relapsed compared with those who did not relapse.
Variables
Age (years) Age at CS diagnosis ≤ 46 years Women Caucasian Black Abnormal echocardiography Decreased LVEF Abnormal myocardial scintigraphy Abnormal myocardial MRI IST Cyclophosphamide Methotrexate
Relapse+ (n = 23)
39 (32—45) 6 (26) 11 (48) 7 (30) 12 (52) 18 (78) 17 (74) 20/23 (87) 19/21 (90) 12 (52) 6 (26) 5 (22)
Relapse− (n = 36)
46 (39—52) 19 (53) 9 (25) 18 (50) 13 (36) 30 (83) 30 (83) 27/33 (82) 25/28 (89) 23 (64) 14 (39) 8 (22)
Univariate analysis
Multivariable analysis
P
OR (95% CI)
0.09 0.06 0.09 0.18 0.28 0.73 0.51 0.72 1.00 0.42 0.40 1.00
P
0.28 (0.08—0.92)0.036 3.2 (0.97—10.5) 0.055
Data are expressed as median (95% confidence interval) or number (%), unless indicated otherwise. CI: confidence interval; IST: immunosuppressive therapy; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; OR: odds ratio; Relapse−: patients who did not relapse; Relapse+: patients who did relapse.
P = 0.04) and in black female patients (relative risk: 3.0; 95% CI: 1.1—8; P = 0.017) (Fig. 3A and B).
Death Five (9%) patients died during follow-up, with two deaths being directly attributable to CS: one sudden death and one death a few days after heart transplantation. The other deaths were the result of asthma (one case), cerebral haemorrhage (one case) and lymphoma (one case).
Discussion The present study reports data from the largest cohort of patients with CS seen in a non-cardiac department. The main conclusions drawn from this study are as follows: CS is usually observed within the field of severe multivisceral sarcoidosis; patients with CS frequently present with unusual clinical and imaging cardiac signs; IST, including steroids, leads to a good prognosis; and long-term followup of patients with CS is mandatory, given the significant risk of relapse.
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C. Chapelon-Abric et al.
Figure 3. Relapse: Kaplan—Meier curve analysis showing the higher risk of cardiac relapse after first-line therapy. A. In black patients. B. In mostly black female patients.
Our series included patients with severe extracardiac sarcoidosis manifestations, as 60% of patients had at least three organ involvements [10]. Neurological involvement was noted in > 50% of cases [2]. These results underline the importance of systematically searching for cardiac manifestations in patients with severe extracardiac sarcoidosis. This strategy permits earlier diagnosis of CS, before abnormal ECG and cardiac symptoms appear. In our series, early diagnosis of CS probably explains the high rate of patients with moderate symptoms [2], as well as the low rate of patients with a decreased left ventricular ejection fraction by MRI (31%) compared with Japanese reports (48—51%) [8,9]. Of note, the ‘‘2006 international criteria’’ appear to be insufficient to detect patients with CS presenting with ‘‘minor’’ cardiological signs [11]. Using only these criteria would have led us to stop our cardiological investigations,
although patients finally proved to have cardiac involvement of sarcoidosis. For example, pericardial effusion is not in the ‘‘2006 international criteria’’, although pericardial biopsies confirmed a granulomatous infiltration; we considered isolated sinus tachycardia (90—110 bpm) as abnormal in the field of systemic disease. Some international criteria are not defined, such as atrial arrhythmias [12]. Other criteria are poorly defined, and are not taken into account: the evaluation of left ventricular ejection fraction (by echocardiography or MRI); isotopic defects and the absence of reversibility during stress or dipyridamole infusion; and the localization and/or nodular aspect of delayed gadolinium enhancement of the myocardium on MRI. The ‘‘2006 international criteria’’ appear useful for patients with severe CS, who are mostly seen in cardiology departments [4,11—13], but, surprisingly, sudden death is not a major criterion. In addition, these criteria do not allow evaluation of the severity of the localization, and do not take into account both CS and extracardiac sarcoidosis. In asymptomatic patients, ECG and echocardiography have low sensitivity and may be normal. All recent publications underline the prognostic and diagnostic values of the FDG PET scan [14—16], eventually associated to scintigraphy [14] and cardiac MRI [17—22]. In a cohort of 71 patients presenting an abnormal PET scan, Blankstein et al. [14] reported 27 ventricular tachycardias and eight deaths after a 1.5-year follow-up. Therefore, a multimodal approach seems mandatory to encompass the diversity of abnormal investigations in sarcoidosis patients with cardiac involvement [11,16,23]; this will also allow the exclusion of other causes of cardiomyopathy. The treatment of CS is challenging, as it always includes cardiac treatments and sometimes immunosuppressants. In our series, all patients received the usual cardiac therapies, including invasive treatment (15% of cases), such as a pacemaker [24], an implantable defibrillator [4,25], radiofrequency ablation [18,21] or cardiac surgery [3,4,26]. The efficacy of steroid treatment for CS has not been evaluated in prospective or controlled studies. However, there is a growing body of evidence to support its efficacy in preserving cardiac function and in treating CS-related cardiac insufficiency [27] and atrioventricular block [13,28] to prevent ventricular tachycardia [29] and improve imaging abnormalities [16,23,30]. The dose of steroids used is mostly between 0.5 and 1.0 mg/kg/day [2,9,11] for a prolonged duration [13]. The role of IST in the therapeutic arsenal of patients with CS remains a matter of debate. Most of our patients received intravenous cyclophosphamide [11]. Tumour necrosis factor antagonists have also been proposed [31,32]. In less severe localizations, and in order to spare steroids, methotrexate proved effective and was well tolerated. Mycophenolate mofetil may also be proposed in such a situation. Of note, in our series, no patient who received IST developed a severe infection or an adverse effect. With the exception of the recent study by Nagai et al. [13], comparing treatment with a low-dose of methotrexate and steroids, there is no comparative study in patients with CS that has demonstrated a survival rate improvement. CS is known to have a bad prognosis, with an estimated mortality rate of up to 50% [6,7]. We and others have shown that in patients who received steroids alone or combined with IST, the 5-year survival rate reached 60—90% [4,8,9,13], with a reduced risk of major adverse cardiac events [33].
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Cardiac sarcoidosis: Diagnosis, therapeutic management and prognostic factors To our knowledge, an analysis of CS relapses and their related factors has never been carried out. A relapse was noted in 39% of our patients, independent of the type of first-line treatment. Two main factors were associated with CS relapses: female sex and black origin, the latter being associated with a more severe disease. Interestingly, these factors are also considered to be associated with a higher risk of sarcoidosis occurrence and a greater severity of systemic sarcoidosis [5]. Study limitations: the present study has some limitations. The retrospective nature of this study is a well-known limitation. Although we report one of the largest series of CS, we acknowledge the need for controlled randomized studies to better define investigation and treatment strategies. We do believe that the cornerstone of CS treatment remains steroid treatment, and that IST should be discussed in cases of severe cardiac or extracardiac disease, for relapse or for steroid-sparing strategies. Another limitation was the small number of patients, but this should be analysed considering the rarity of CS. To respect the ‘‘2006 international criteria’’, we excluded patients with cardiac signs and probable CS in 69 cases. This raises the question about the type of investigations for CS early diagnosis, as the use of cardiac MRI and PET scans may show very early morphological and functional abnormalities without an ECG abnormality [23]. The new consensus statement on the diagnosis and management of arrhythmias associated with CS may help to include CS [34].
Conclusions In conclusion, in this large series of patients, CS has a good prognosis, with an overall 5-year survival rate of 92%. The recovery rate was > 75%, with no significant difference between patients treated with steroids alone or steroids plus IST. Close monitoring is mandatory, particularly in female or black patients, as they appear to be at higher risk of relapse. Immunosuppressant maintenance treatment was well tolerated, and certainly helped to stabilize the granulomatosis, which cannot be cured.
Sources of funding None.
Acknowledgements D. Sène and C. Chapelon-Abric acquired and analysed data, wrote and critically revised the manuscript and provided final approval of the version to be published. D. Saadoun, N. Costedoat-Chalumeau, J.-C. Piette and P. Cacoub included patients in the study, critically revised the manuscript and provided final approval of the version to be published. P. Cluzel and O. Vignaux reviewed cardiac MRI data, critically revised the manuscript and provided final approval of the version to be published.
Disclosure of interest The authors declare that they have no competing interest.
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